Polyamines are considered essential in cell proliferation. The naturally occurring polyamines in mammalian cells are putrescine, spermidine and spermine. A wide variety of related amines are found in other organisms and may play critical roles in their physiology. Nevertheless, it is also known that the association of cationic polyamines with negatively charged DNA induces significant structural changes in DNA. Spermidine and spermine can cause DNA to condense and aggregate and induce reversible B-to-Z transition in certain DNA sequences (Marton, L. J. et al., Annu. Rev. Pharmacol. Toxicol., 1995, 35: 55-91). This led the researches to focus their attention on the potential use of polyamines as antitumor drugs (Basu, H. S. et al., Biochem. J., 1990, 269: 329-334; Yanlong Li et al., J. Med. Chem., 1996, 39: 339-341).
In spite of the scientific interest raised in the last years by these compounds, relatively few papers have been published describing their synthesis.
The preparation of the spermine and spermidine analogues has been mainly accomplished up to now by condensing a diamine with acrylonitrile and by reducing the nitrile group via catalytic hydrogenation (J. Med. Chem., 7, 710-16 (1964); U.S. Pat. No. 5,097,072; U.S. Pat. No. 4,967,008; J. Pharm. Sciences, 70(8), 956-9 (1981)). The main limitation of this method is that using acrylonitrile only 3-C terminal amine chains are obtained. Other drawbacks are due to the difficulty of purification of the final compounds, which is often performed by vacuum distillation. In particular, when dicyanoethylated compounds are desired, they undergo extensive decomposition on distillation and therefor cannot be obtained in a pure form using this method. The toxicity of acrylonitrile, increased by its high volatility, may be another problem, especially in view of a large scale synthesis.
A further method that has been reported for the preparation of polyamines is the reduction of amide intermediates which can be obtained by condensing .omega.-amino acids with diamines or of .alpha.,.omega.-diacids with two equivalents of diamine (J. Med. Chem., 31, 1183-1190 (1988)). However we have found that this method does not allow to prepare with good yields all the derivatives, since especially the lower alkylenyl homologues give by-products in large amount during the reduction step.
More recently the preparation of unsymmetrically substituted polyamine analogues was also reported (J. Med. Chem., 36, 2998-3004 (1993)). However the described process does need the preparation of rather complex synthons containing simultaneously three different nitrogen protecting groups. This results in a long multistep procedure which is unsuitable for industrial purposes. Moreover, the use of a mesityl protecting group is also unsuitable, since it requires acidic conditions for cleavage which can largely impair the flexibility of the method.
We have now found a new advantageous process for synthesizing polyamine derivatives.